Update on Regulatory Developments around the
eCTD in Europe and the Quantum Leap ahead
for South Africa
16 November 2012
Henriette Vienings
• Introduction
• Developments in 2012
• Paperless Regulatory Authorities
• Software Vendors
• Submission Ready Documents
• Acknowledgements:
• Knowledge shared today is knowledge gained at Lorenz' User
Conference in Ireland in September 2012 and through the work we
do at MRA Regulatory Consultants (MRA) on a daily basis.
• Thank you SAPRAA for the opportunity to present here today.
• MRA is a docuBridge user and snapshots of builder
images are taken from our compilation environment.
Developments in 2012
• In fact – not just in Europe… - ICH driven activity = Global
• Canada
• Other regions
• eCTD 4 / eCTD NMV – ICH M8, Endorsed 11 Nov. 2010
• eCTD 4 = The next major version (NMV) of the eCTD
• The challenge: to continue supporting the current ICH eCTD v3.2.2
and STF v2.6.1 requirements
• Implementation Plan for eCTD4 – in 4 Steps
• Currently in Step 2 – Testing of the ICH eCTD v4.0 DRAFT
Implementation Guide v1.0 as of June 2012 – March 2013.
• Subgroup to M2 Expert Working Group (EWG) responsible for the
eCTD Specifications
eCTD 4 / eCTD NMV &
Regulated Product Submission (RPS)
• Setting the scene for document reusability, interoperability
between builders and shared review (- the brave new
• Universally Unique Identifiers (UUI)
• for sequences in each application
• for each individual file
• for communication between Agency and Applicant – portal environment
• Controlled Vocabulary (CV) – harmonising terminology
• Drug Substance, Active Substance, Active Ingredient
• Drug Product, Finished Product
eCTD 4 / eCTD NMV &
Regulated Product Submission (RPS)
• Functional improvements
Sequence Replication – content reusability
Regulatory Activity – grouping sequences that apply to one activity
Access to the entire application from any part of the application
Capability to identify which eCTD sequence was used at which step of agency
• Cross-referencing files across different sequences in one product’s lifecycle
and, or across different products
• Compatibility across regions and across the regional lifecycling methodology /
eCTD 4 / eCTD NMV &
Regulated Product Submission (RPS)
• Maintaining similarity to the current eCTD file-leaf model
in the eCTD NMV with the following exceptions:
• Lifecycle changes to existing documents will allow only:
• New
• Replace
• Delete
• Appending documents will no longer be possible.
• Supporting changes in granularity.
eCTD 4 / eCTD NMV &
Regulated Product Submission (RPS)
• Validation improvements:
• ensure that the document specification (DTD) remains unchanged –
MD5 checksums
Should ensure that all files submitted are defined and referenced
Support the use of controlled vocabularies for both harmonised
metadata and regional metadata
Specify date values in an unambiguous manner
Integrity of electronic files within an instance
Will not negate previous versions of the eCTD. These should remain
valid submissions and reviewing tools should be able to review
submissions made in terms of eCTD 3.2x specifications even if they are
enabled for eCTD NMV.
eCTD 4 / eCTD NMV &
Regulated Product Submission (RPS)
• Data transfer
• Applicant  Regulatory Authority / Regulatory Authority 
• No restriction on mechanism for transmitting - media type/network
• Supporting 2-way communication
• Enabling acknowledgement of receipt
• Traceability and relationship between activities and sequence
• eCTD Tools Interoperability and Compliance Study
• ICH study of eCTD tools to look at the issues of:
• Interoperability:
• Can an eCTD created by one tool be opened and used by another?
• Compliance:
• Is the eCTD compliant with ICH and regional requirements?
• 11 Tools were tested
Bryan Ennis – userBridge 2012
• Launched February 2010 as a project of the IRISS
Interoperability Group
IRISS = Implementation of Regulatory Information Submission Standards
• Questions/departure points for ETICS III:
• How are systems, that are capable of meeting
regulatory requirements, enable collaboration and
establish traceability of content, enabled?
Bryan Ennis – userBridge 2012
• Current IT technology advances such as Cloud-based
systems and mobile devices, are emerging to enable
globally-distributed staff to acquire, create, and manage
regulated content that is universally accessible,
reportable, and is extensible.
• ETICS III is qualifying the interoperability and validation
capabilities of current regulatory submission
technologies – the CTD builders (as we know them).
Bryan Ennis – userBridge 2012
Further Developments in Europe - 2012
• Late in 2010, EC Directives were implemented in an effort
to improve the safeguards to public health.
• The regulations mandated that the EU Agencies have and
maintain databases for medicinal products that:
• Provide access to the approved package leaflets in language that
is considered to be understandable to the reader.
• Access must be granted to:
all Member States
the general public
health-care professionals
marketing authorisation holders (MAH)
Karl-Heinz Loebel – userBridge 2012
Further Developments in 2012
• 2 July 2012 was the deadline for MAHs to electronically
submit the required information to the Agencies
• The technical specifications of which were published in
March 2012 by the EMA – all 401 pages of it…
• 2 Technical Environments:
• EudraVigilance Production Environment
• EudraVigilance External Compliance Testing (XCOMP)
Karl-Heinz Loebel – userBridge 2012
Further Developments in 2012
• The database generated enables:
• traceability of any of the following - in the event of a technical
concern, counterfeit alert, adverse reaction / pharmacovigilance
• Active Substances
• Excipients
• Manufacturers
• Marketing Authorisation Holders
• corrective and preventive action to be taken by an Agency where
for example; suspect quality of an active substance can be traced
to all products that could potentially be affected - throughout the
European Region.
Karl-Heinz Loebel – userBridge 2012
Further Developments in 2012
• Nutzendossier (Value Dossier) – Germany
• Requires the submission of pharmaco-economic studies and data
as motivation for the need for the product in the market place
• To be submitted at the time of submitting an application for
• Currently not a requirement for submissions made into the EMA –
Centralised Procedure for Mutual Recognition
Further Developments in 2012
• By 2013 the German Regulatory Authorities will no longer
accept paper submissions.
• What will this mean for the EMA for whom the German
Authority is a vitally important Rapporteur and technical
• EDQM has been paperless since 2010.
• The NEES seems finally to have been abandoned.
TPD = Therapeutic Products Directorate
BGTD = Biologics & Genetic Therapies Directorate
Vianney Caron – Health Canada @ userBridge 2012
Software Vendors
• CTD builders are critical in alleviating the admin burden
involved in compiling submissions. They reduce mistakes and
allow us to reuse our data.
• Manage to integrate the ever-changing submission
requirements globally into their tools.
• Keep up to date with the regional specifications and provide the
validation tools.
• Provide databases that are customised to the regulatory
environment and help us manage the information that we are
the custodians of.
• Provide valuable training from a “futuristic” perspective which
helps us to think and plan ahead.
Submission Ready Documents
• Think of the future - Think eCTD!
• Granulate and name in accordance with ICH requirements and
the regional requirements.
• Ensure that you will not need to rework documents
unnecessarily in the future.
• It may take a little bit more time to do this, but you can train
administrative assistants to help with this work.
Submission Ready Documents • Granulate and name in accordance with ICH
ICH M2 EWG 2008, Appendix 4: File Organisation of the eCTD
Submission Ready Documents - ICH
• PDF:
• Version 1.4 – Agencies don’t need additional software to view
• Should be rendered not images/scans
• Optical Character Recognition (OCR) enabled
• Not secured / password protected
• one should be able to select, copy and paste sections out of a document
into another document if needed.
• Secured/protected documents fail validation!
• Minimum resolution – text 300 dpi (dots per inch); photos 600 dpi
• Do not shrink documents/reduce size at the cost of legibility or quality.
• Compress for storage or transfer purposes if needed.
ICH M2 EWG – eCTD Specifications, 16 July 2008
Submission Ready Documents - ICH
• Fonts:
• Ensure that only standard fonts are used
• Embed fonts
• Text size – minimum size equivalent to Times New Roman 12
• Table text size – minimum size equivalent to Times New Roman 10
Company logos are not to be inserted into headers/footers. - Even if the
logo is only 5b in size, imagine that multiplied across a 50 000 page
Company logos are acceptable on letterheads and signed reports.
ICH M2 EWG – eCTD Specifications, 16 July 2008
The Quantum Leap…
The Quantum Leap…
A change in perspective… and a change in attitude!
The future of regulatory compliance is the eCTD.
We need to ensure that we have the right tools and the
right people to do the work in an ever-evolving
It’s time to engage!
Thank You!
Or maybe later…
[email protected]

similar documents